FERM domain-containing unconventional myosin VIIA interacts with integrin β5 subunit and regulates αvβ5-mediated cell adhesion and migration

AbstractUnconventional myosin VIIA (Myo7a) has been known to associate with hereditary deafness. Here we present a novel function of Myo7a by identifying that Myo7a directly interacts with integrin β5 subunit and regulates cell adhesion and motility in an integrin-dependent manner. We found that Myo7a bound to the cytoplasmic tail of integrin β5. Further, we pinpointed an integrin-binding domain at F3 of the first FERM domain and F1 of the second FERM domain. Functionally, Myo7a-induced cell adhesion and migration were mediated by integrin αvβ5. These findings indicated that Myo7a interacts with integrin β5 and selectively promotes integrin αvβ5-mediated cell migration

Ferroptosis-associated circular RNAs: Opportunities and challenges in the diagnosis and treatment of cancer

Ferroptosis is an emerging form of non-apoptotic regulated cell death which is different from cell death mechanisms such as autophagy, apoptosis and necrosis. It is characterized by iron-dependent lipid peroxide accumulation. Circular RNA (circRNA) is a newly studied evolutionarily conserved type of non-coding RNA with a covalent closed-loop structure. It exhibits universality, conservatism, stability and particularity. At present, the functions that have been studied and found include microRNA sponge, protein scaffold, transcription regulation, translation and production of peptides, etc. CircRNA can be used as a biomarker of tumors and is a hotspot in RNA biology research. Studies have shown that ferroptosis can participate in tumor regulation through the circRNA molecular pathway and then affect cancer progression, which may become a direction of cancer diagnosis and treatment in the future. This paper reviews the molecular biological mechanism of ferroptosis and the role of circular RNA in tumors and summarizes the circRNA related to ferroptosis in tumors, which may inspire research prospects for the precise prevention and treatment of cancer in the future

Oxidative Stress Activated by Sorafenib Alters the Temozolomide Sensitivity of Human Glioma Cells Through Autophagy and JAK2/STAT3-AIF Axis

The development of temozolomide (TMZ) resistance in glioma leads to poor patient prognosis. Sorafenib, a novel diaryl urea compound and multikinase inhibitor, has the ability to effectively cross the blood-brain barrier. However, the effect of sorafenib on glioma cells and the molecular mechanism underlying the ability of sorafenib to enhance the antitumor effects of TMZ remain elusive. Here, we found that sorafenib could enhance the cytotoxic effects of TMZ in glioma cells in vitro and in vivo. Mechanistically, the combination of sorafenib and TMZ induced mitochondrial depolarization and apoptosis inducing factor (AIF) translocation from mitochondria to nuclei, and this process was dependent on STAT3 inhibition. Moreover, the combination of sorafenib and TMZ inhibited JAK2/STAT3 phosphorylation and STAT3 translocation to mitochondria. Inhibition of STAT3 activation promoted the autophagy-associated apoptosis induced by the combination of sorafenib and TMZ. Furthermore, the combined sorafenib and TMZ treatment induced oxidative stress while reactive oxygen species (ROS) clearance reversed the treatment-induced inhibition of JAK2/STAT3. The results indicate that sorafenib enhanced the temozolomide sensitivity of human glioma cells by inducing oxidative stress-mediated autophagy and JAK2/STAT3-AIF axis

Low glucose and metformin-induced apoptosis of human ovarian cancer cells is connected to ASK1 via mitochondrial and endoplasmic reticulum stress-associated pathways

Abstract Background Metformin, a first-line drug for type 2 diabetes, could induce apoptosis in cancer cells. However, the concentration of glucose affects the effect of metformin, especially low glucose in the culture medium can enhance the cytotoxicity of metformin on cancer cells. Since mitochondria and endoplasmic reticulum is vital for maintaining cell homeostasis, we speculate that low glucose and metformin-induced cell apoptosis may be associated with mitochondria and endoplasmic reticulum. ASK1, as apoptosis signaling regulating kinase 1, is associated with cell apoptosis and mitochondrial damage. This study was designed to investigate the functional significance of ASK1, mitochondria and endoplasmic reticulum and underlying mechanism in low glucose and metformin-induced cell apoptosis. Methods An MTT assay was used to evaluate cell viability in SKOV3, OVCAR3 and HO8910 human ovarian cancer cells. Cell apoptosis was analyzed by flow cytometry. The expression of ASK1 was inhibited using a specific pharmacological inhibitor or ASK1-siRNA. Immunofluorescence was used to detect mitochondrial damage and ER stress. Nude mouse xenograft models were given metformin or/and NQDI-1, and ASK1 expression was detected using immunoblotting. In addition, subcellular fractionation of mitochondria was performed to assay the internal connection between ASK1 and mitochondria. Results The present study found that low glucose in culture medium enhanced the anticancer effect of metformin in human ovarian cancer cells. Utilization of a specific pharmacological inhibitor or ASK1-siRNA identified a potential role for ASK1 as an apoptotic protein in the regulation of low glucose and metformin-induced cell apoptosis via ASK1-mediated mitochondrial damage through the ASK1/Noxa pathway and via ER stress through the ROS/ASK1/JNK pathway. Moreover, ASK1 inhibition weakened the antitumor activity of metformin in vivo. Thus, mitochondrial damage and ER stress play a crucial role in low glucose–enhanced metformin cytotoxicity in human ovarian cancer cells. Conclusions These data suggested that low glucose and metformin induce cell apoptosis via ASK1-mediated mitochondrial damage and ER stress. These findings indicated that the effect of metformin in anticancer treatment may be related to cell culture conditions

Detoxification of DON-induced hepatotoxicity in mice by cold atmospheric plasma

Deoxynivalenol (DON) is one of the most common mycotoxins distributed in food and feed, which causes severe liver injury in humans and animals. Cold atmospheric plasma (CAP) has received much attention in mycotoxin degradation due to the advantages of easy operation, high efficiency, and low temperature. So far, the majority of studies have focused on the degradation efficiency and mechanism of CAP on DON, while there is still little information available on the hepatotoxicity of DON after CAP treatment. Herein, this study aimed to investigate the effect of CAP on DON-induced hepatotoxicity both in vitro and in vivo and its underlying mechanisms. The results showed that 120-s CAP treatment achieved 97 % degradation of DON. The vitro hepatotoxicity of DON in L02 cells was significantly reduced with CAP treatment time. Meanwhile, CAP markedly alleviated DON-induced liver injury in mice including the balloon-like degeneration of liver tissues and elevation of AST and ALP level. The underlying mechanism for CAP detoxification of DON-induced hepatotoxicity was further elucidated. The results showed that DON caused severe oxidative stress in cells by suppressing the antioxidant signaling pathway of Nrf2/HO-1/NQO-1, consequently leading to mitochondrial dysfunction and cell apoptosis, accompanied by cellular senescence and inflammation. CAP blocked DON inhibition on the Nrf2/HO-1/NQO-1 signaling pathway through the efficient degradation of DON, accordingly alleviating the oxidative stress and liver injury induced by DON. Therefore, CAP is an effective method to eliminate DON hepatotoxicity, which can be applied in the detoxification of mycotoxin-contaminated food and feed to ensure human and animal health

RNA methylation‐related inhibitors: Biological basis and therapeutic potential for cancer therapy

Abstract RNA methylation is widespread in nature. Abnormal expression of proteins associated with RNA methylation is strongly associated with a number of human diseases including cancer. Increasing evidence suggests that targeting RNA methylation holds promise for cancer treatment. This review specifically describes several common RNA modifications, such as the relatively well‐studied N6‐methyladenosine, as well as 5‐methylcytosine and pseudouridine (Ψ). The regulatory factors involved in these modifications and their roles in RNA are also comprehensively discussed. We summarise the diverse regulatory functions of these modifications across different types of RNAs. Furthermore, we elucidate the structural characteristics of these modifications along with the development of specific inhibitors targeting them. Additionally, recent advancements in small molecule inhibitors targeting RNA modifications are presented to underscore their immense potential and clinical significance in enhancing therapeutic efficacy against cancer. Key Points In this paper, several important types of RNA modifications and their related regulatory factors are systematically summarised. Several regulatory factors related to RNA modification types were associated with cancer progression, and their relationships with cancer cell migration, invasion, drug resistance and immune environment were summarised. In this paper, the inhibitors targeting different regulators that have been proposed in recent studies are summarised in detail, which is of great significance for the development of RNA modification regulators and cancer treatment in the future